Sulfonyl-phenyl-2h-[1,2,4]oxadiazol-5-one derivatives , processes for their preparation and their use as pharmaceuticals

ABSTRACT

The invention relates to sulfonyl-phenyl-oxadiazolones and to their physiologically acceptable salts and physiologically functional derivatives showing PPARdelta or PPARdelta and PPARgamma agonist activity. 
     What are described are compounds of the formula I, 
     
       
         
         
             
             
         
       
     
     in which the radicals are as defined, and their physiologically acceptable salts and processes for their preparations. The compounds are suitable for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders as well as of disorders in which insulin resistance is involved and demyelinating and other neurodegenerative disorders of the central and peripheral nervous system.

This application is a Continuation of International Application No.PCT/EP2007/010390, filed Nov. 30, 2007, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to sulfonyl-phenyl-oxadiazolones and to theirphysiologically acceptable salts and physiologically functionalderivatives showing PPARdelta or PPARdelta and PPARalpha agonistactivity.

BACKGROUND OF THE INVENTION

PPARdelta agonists having a sulfonamide group are described in WO2003/097607, WO 2004/005253 and DE 10335449 as well as in WO2004/092117. Compounds comprising an oxadiazolone feature are disclosedin WO 2005/097786.

The invention was based on the object of providing compounds whichpermit therapeutically utilizable modulation of lipid and/orcarbohydrate metabolism and are thus suitable for the prevention and/ortreatment of diseases such as type 2 diabetes and atherosclerosis andthe diverse sequelae thereof. Another purpose of the invention is totreat demyelinating and other neurodegenerative disorders of the centraland peripheral nervous systems.

A series of compounds which modulate the activity of PPA receptors hasbeen found. The compounds are suitable in particular for activatingPPARdelta or PPARdelta and PPARalpha, however it is possible that therelative activation varies depending on the specific compounds.

SUMMARY OF THE INVENTION

Compounds of the present invention are described by formula I:

whereinn is 0, 1R1, R2 are independently H, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7)cycloalkyl, (C0-C4) alkylene —(C6-C10) aryl, wherein alkyl and alkyleneare unsubstituted or 1- to 3-fold substitued by F;R3, R4 are independently H, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7)cycloalkyl, (C0-C4) alkylene —(C6-C10) aryl, wherein alkyl and alkyleneare unsubstituted or 1- to 3-fold substitued by F;R5,R6 are independently H, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7)cycloalkyl, (C0-C4) alkylene —(C6-C10) aryl, wherein alkyl and alkyleneare unsubstituted or 1- to 3-fold substitued by F; orR5 and R6 together with the carbon atom carrying them form a (C3-C7)cycloalkylring, wherein one carbon atom can be replaced by oneheteroatom O, S, N;R7 is H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H,(C3-C7) cycloalkyl, wherein alkyl and alkylene are unsubstituted or 1-to 3-fold substitued by F;R8, R9 are independently H, halogen, (C1-C8) alkyl, (C0-C4)alkylene-O—(C0-C4) alkylene-H, (C3-C7) cycloalkyl,—CO—O—(C0-C4)-alkylene-H, CO—O-phenyl, —C0-NR12R13, wherein alkyl andalkylene are unsubstituted or 1- to 3-fold substitued by F, NR12R13 andphenyl is unsubstituted or 1- to 3-fold substituted by halogen, (C1-C4)alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, or NR12R13; orR8 and R9 together with the carbon atoms to which they are bonded form a(C5-C7) cycloalkyl ring, wherein one carbon atom can be replaced by oneheteroatom O, S, N;R10, R11 are independently H, halogen, (C1-C8) alkyl, (C0-C4)alkylene-O—(C0-C4) alkylene-H, (C3-C7) cycloalkyl, (C6-C10) aryl,wherein cycloalkyl and aryl are unsubstituted or 1- to 2-foldsubstituted by (C1-C4) alkyl and wherein alkyl and alkylene areunsubstituted or 1- to 3-fold substitued by F;R12, R13 are independently H, (C1-C6) alkyl;in all its stereoisomeric forms and mixtures in any ratio, and itsphysiologically acceptable salts and tautomeric forms.

DETAILED DESCRIPTION OF THE INVENTION

Another embodiment according to the invention are compounds of theformula I, wherein

n is 0, 1R1, R2 are independently H, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7)cycloalkyl, (C0-C4) alkylene —(C6-C10) aryl, wherein alkyl and alkyleneare unsubstituted or 1- to 3-fold substitued by F;R3,R4 are independently H, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7)cycloalkyl, (C0-C4) alkylene —(C6-C10) aryl, wherein alkyl and alkyleneare unsubstituted or 1- to 3-fold substitued by F;R5,R6 are independently H, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7)cycloalkyl, (C0-C4) alkylene —(C6-C10) aryl, wherein alkyl and alkyleneare unsubstituted or 1- to 3-fold substitued by F;R7 is H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H,(C3-C7) cycloalkyl, wherein alkyl and alkylene are unsubstituted or 1-to 3-fold substitued by F;R8, R9 are independently H, halogen, (C1-C8) alkyl, (C0-C4)alkylene-O—(C0-C4) alkylene-H, (C3-C7) cycloalkyl, wherein alkyl andalkylene are unsubstituted or 1- to 3-fold substitued by F;R10, R11 are independently H, halogen, (C1-C8) alkyl, (C0-C4)alkylene-O—(C0-C4) alkylene-H, (C3-C7) cycloalkyl, wherein alkyl andalkylene are unsubstituted or 1- to 3-fold substitued by F;

Another embodiment according to the invention are compounds of theformula I, wherein

n is 0.

Another embodiment according to the invention are compounds of theformula I, wherein

n is 1.

Another embodiment according to the invention are compounds of theformula I, wherein

R9 is in position 2.

Another embodiment according to the invention are compounds of theformula I, wherein

R9 is in position 3 if R8 and R9 together with the carbon atoms to whichthey are bonded form a cycloalkyl ring.

Another embodiment according to the invention are compounds of theformula I, wherein

R11 is in position 3′.

Another embodiment according to the invention are compounds of theformula I, wherein

R11 is in position 3′ and

R10 is H.

Another embodiment according to the invention are compounds of theformula I, wherein

R8 is CF₃.

Another embodiment according to the invention are compounds of theformula I, wherein

R10 is Cl.

Another embodiment according to the invention are compounds of theformula I, wherein

R5 and R6 together with the carbon atom carrying them form a (C3-C7)cycloalkyl ring, wherein one carbon atom can be replaced by oneheteroatom O, S, N, preferably by one heteroatom O.

Another embodiment according to the invention are compounds of theformula I where one or more substituents have the following meaning:

n is 0, 1;

R1, R2 are H; R3, R4 are H;

R5, R6 are independently H, (C1-C6) alkyl, preferably, H, CH₃; orR5 and R6 together with the carbon atom carrying them form a (C5-C6)cycloalkyl ring wherein one carbon atom can be replaced by oneheteroatom O or N, preferably it forms a tetrahydropyran ring;

R7 is H; R8 is CF₃, Cl;

R9 is in position 2 and

R9 is H, F, O—(C1-C4) alkyl, COOH, CO—O-phenyl, O—(C1-C4) alkyl-NR12R13,CO—O—(C1-C4) alkyl-NR12R13, CO—NH—(C1-C4) alkyl-NR12R13; orR8 and R9 together with the carbon atoms to which they are bonded form a(C5-C6) cycloalkyl ring, wherein one carbon atom is replaced by oneheteroatom O;

R10 is H, Cl, F, CH₃;

R11 is H, Cl, phenyl-CF₃;R12, R13 are (C1-C4) alkyl.

Another embodiment according to the invention are compounds of theformula I where one or more substituents have the following meaning:

n is 0, 1;

R1, R2 are H; R3, R4 are H;

R5, R6 are independently H, (C1-C6) alkyl, preferably, H, CH₃; orR5 and R6 together with the carbon atom carrying them form a (C5-C6)cycloalkyl ring wherein one carbon atom is replaced by one heteroatom O,preferably a tetrahydropyran ring;

R7 is H; R8 is CF₃, Cl;

R9 is H, O—(C1-C4) alkyl, COOH, CO—O-phenyl, preferably H, methoxy,COOH, CO—O-phenyl; orR8 and R9 together with the carbon atoms to which they are bonded form a(C5-C6) cycloalkyl ring, wherein one carbon atom is replaced by oneheteroatom O;

R10 is H, Cl;

R11 is H, Cl, phenyl-CF₃;R12, R13 are (C1-C4) alkyl, preferably methyl.

Another embodiment according to the invention are compounds of theformula I where one or more substituents have the following meaning:

n is 0, 1;

R1, R2 are H; R3, R4 are H;

R5, R6 are independently H, (C1-C6) alkyl, preferably, H, CH₃;

R7 is H;

R8 is CF₃; R9 is H; R10 is Cl; R11 is H.

Another embodiment according to the invention are compounds of theformula I where one or more substituents have the following meaning:

R1, R2 are H; R3, R4 are H;

R5, R6 are independently H, (C1-C6) alkyl, preferably, H, CH₃;

R7 is H; R8 is CF₃; R9 is H, F; R10 is H, Cl, F, CH₃; R11 is H.

Another embodiment according to the invention are compounds of theformula I where one or more substituents have the following meaning:

R5 is H and R6 is H or R5 is CH₃ and R6 is CH₃; R9 is H; R10 is H, Cl.

Further embodiments according to the invention are the followingcompounds:

-   3-{4-[5-(4-Trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one-   3-{4-[3,3-Dimethyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-one-   3-{2-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one-   3-{2-Chloro-4-[3,3-dimethyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-one-   3-{2-Chloro-4-[7-(4-trifluoromethyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-one-   3-{3-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one-   3-{4-[5-(2-Methoxy-4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one-   5-Chloro-2-{1-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-2,3-dihydro-1H-indol-5-yl}-benzoic    acid phenyl ester-   5-Chloro-2-{1-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-2,3-dihydro-1H-indol-5-yl}-benzoic    acid-   3-{4-[5-(2,3-Dihydro-benzofuran-5-yl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one-   3-{4-[3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one-   3-{4′-Trifluoromethyl-6-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-biphenyl-3-yl}-4H-[1,2,4]oxadiazol-5-one-   3-(4-{5-[2-(2-Dimethylamino-ethoxy)-4-trifluoromethyl-phenyl]-2,3-dihydro-indole-1-sulfonyl}-phenyl)-4H-[1,2,4]oxadiazol-5-one-   2-{1-[4-(5-Oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-2,3-dihydro-1H-indol-5-yl}-5-trifluoromethyl-benzoic    acid 2-dimethylamino-ethyl ester-   N-(2-Dimethylamino-ethyl)-2-{1-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-2,3-dihydro-1H-indol-5-yl}-5-trifluoromethyl-benzamide

This invention also encompasses all combinations of preferred aspects ofthe invention described herein.

As used herein, the term alkyl is to be understood in the broadest senseto mean saturated hydrocarbon residues which can be linear, i.e.straight-chain, or branched. If not otherwise defined alkyl has 1 to 8carbon atoms. Examples of “—(C1-C8)-alkyl” are alkyl residues containing1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms are methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl or octyl, the n-isomers of all these residues,isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl,2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl,tert-butyl or tert-pentyl. The term “—(C0-C8)-alkyl” is a hydrocarbonresidue containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, in which theterm “—CO-alkyl” is a covalent bond. All these statements apply also tothe term alkylene.

As used herein, the term alkenyl is to be understood in the broadestsense to mean hydrocarbon residues which has 1 to 4 double bonds and canbe linear, i.e. straight-chain, or branched. If not otherwise definedalkenyl has 2 to 8 carbon atoms. Examples of “—(C2-C8)-alkenyl” arealkenyl residues containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms are, forexample vinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl, 3-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl.All these statements apply also to the term alkenylene.

As used herein, the term alkinyl is to be understood in the broadestsense to mean hydrocarbon residues, which has 1 to 4 triple bonds andcan be linear, i.e. straight-chain, or branched. If not otherwisedefined alkinyl has 2 to 8 carbon atoms. Examples of “—(C2-C8)-alkinyl”are alkinyl residues containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms are,for example ethynyl, 1-propynyl, 2-propynyl (=propargyl) or 2-butynyl.All these statements apply also to the term alkylidene.

All these statements also apply if an alkyl group occurs as asubstituent on another residue, for example in an alkyloxy residue, analkyloxycarbonyl residue or an arylalkyl residue.

If not otherwise defined, alkyl, and alkylene, are unsubstituted ormono, di- or trisubstituted independently of one another by suitablegroups such as, for example: F, Cl, Br, I, CF3, NO2, CN, COOH,CO—O—(C0-C4) alkylene-(C6-C10) aryl, CO—O—(C1-C4) alkyl, CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl, CO—O—(C0-C4) alkylene-(C3-C15)heterocycle,CO—N((C0-C4) alkylene-H)—(C0-C4) alkylene-(C6-C10) aryl, CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-H, CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl, CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C15) heterocycle, (C0-C4) alkylene-(C3-C6)cycloalkyl,(C0-C4) alkylene-(C6-C10)aryl, (C0-C4) alkylene-(C3-C15)heterocycle,(C2-C6)-alkenyl, (C2-C6)-alkinyl, O—(C0-C6)-alkyl, O—(C0-C4)alkylene-(C6-C10) aryl, O—(C0-C4) alkylene-(C3-C12)cycloalkyl, O—(C0-C4) alkylene-(C3-C15)heterocycle, O—CO—O—(C0-C4) alkylene-(C6-C10)aryl, O—CO—O—(C1-C4) alkyl, O—CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl,O—CO—O—(C0-C4) alkylene-(C3-C15)heterocycle, S—(C1-C4)alkyl, S—(C0-C4)alkylene-(C3-C13)cycloalkyl, S—(C0-C4) alkylene-(C6-C10) aryl, S—(C0-C4)alkylene-(C3-C15) heterocycle, SO—(C1-C4)alkyl, SO—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO—(C0-C4) alkylene-(C6-C10) aryl,SO—(C0-C4) alkylene-(C3-C15) heterocycle, SO2—(C1-C4)alkyl, SO2—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO2—(C0-C4) alkylene-(C6-C10) aryl,SO2—(C0-C4) alkylene-(C3-C15) heterocycle,SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C10)aryl,SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-H, SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, where thearyl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H;N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, N((C0-C4)alkylene-H)—(C0-C4)alkylene-H)—(C1-C6)cycloalkyl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle,where the aryl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, SO2—CH3, COOH,COO—(C1-C6)-alkyl, SF5, CONH2.

If not otherwise specified, the term cycloalkyl is to be understood tomean saturated hydrocarbon cycle containing from 3 to 13 carbon atoms ina mono- or bicyclic, fused, bridged or spirocyclic ring. Examples of(C3-C13)-cycloalkyl cyclic alkyl residues are cycloalkyl residuescontaining 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 ring carbon atoms likecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl or cyclododecyl. Theterm cycloalkyl also includes bicyclic groups in which any of the abovecycloalkyl ring is fused to a benzene ring, for example indane and1,2,3,4-tetrahydronaphthalene.

If not otherwise defined cycloalkyl are unsubstituted or mono, di- ortrisubstituted independently of one another by suitable groups such as,for example: F, Cl, Br, I, CF3, NO2, CN, COOH, CO—O—(C0-C4)alkylene-(C6-C10) aryl, CO—O—(C1-C4) alkyl, CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl, CO—O—(C0-C4) alkylene-(C3-C15)heterocycle,CO—N((C0-C4) alkylene-H)—(C1-C6)alkylene-H, CO—N((C0-C4)alkylene-H)—(C1-C6)cycloalkyl, CON((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl, (C0-C4)alkylene-(C3-C6)cycloalkyl, (C3-C6)alkyl, (C2-C6)-alkenyl,(C2-C6)-alkinyl, (C0-C4) alkylene-(C6-C10)aryl, (C0-C4)alkylene-(C3-C15)heterocycle, O—(C0-C6)-alkyl, (C0-C4)alkylene-O—(C0-C4) alkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C13)cycloalkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C6-C10)aryl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C15)heterocycle, O—CO—O—(C0-C4) alkylene-(C6-C10) aryl,O—CO—O—(C1-C4) alkyl, O—CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl,O—CO—O—(C0-C4) alkylene-(C3-C15)heterocycle, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-(C6-C10) aryl, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-H, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C15) heterocycle, S—(C1-C4)alkyl, S—(C0-C4)alkylene-(C3-C13)cycloalkyl, S—(C0-C4) alkylene-(C6-C10) aryl, S—(C0-C4)alkylene-(C3-C15) heterocycle, SO—(C1-C4)alkyl, SO—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO—(C0-C4) alkylene-(C6-C10) aryl,SO—(C0-C4) alkylene-(C3-C15) heterocycle, SO2—(C1-C4)alkyl, SO2—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO2—(C0-C4) alkylene-(C6-C10) aryl,SO2—(C0-C4) alkylene-(C3-C15) heterocycle,SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C10)aryl,SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-H, SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, where thearyl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O —(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H;N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, N((C0-C4)alkylene-H)—(C0-C4)alkylene-H)—(C1-C6)cycloalkyl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle,where the aryl or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O —(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, SO2—CH3, COOH,COO—(C1-C6)-alkyl, SF5, CONH2.

The term “aryl” is understood to mean aromatic hydrocarbon ringcontaining from 6 to 14 carbon atoms in a mono- or bicyclic ring.Examples of (C6-C14)-aryl rings are phenyl, naphthyl, for example1-naphthyl and 2-naphthyl, biphenylyl, for example 2-biphenylyl,3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl. Biphenylyl rings,naphthyl rings and, in particular, phenyl rings are further embodimentsof aryl rings.

The terms heterocycle is understood to mean saturated(heterocycloalkyl), partly unsaturated (heterocycloalkenyl) orunsaturated (heteroaryl)hydrocarbon rings containing from 3 to 15 carbonatoms in a mono- or bicyclic, fused, bridged or spirocyclicring in which1 to 5 carbon atoms of the 3 to 15 ring carbon atoms are replaced byheteroatoms such as nitrogen, oxygen or sulfur in which further theheteroatoms can be oxidized, for example N═O, S═O, SO2. Examples ofheterocycles are acridinyl, azaindole (1H-pyrrolopyridinyl),azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl,benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydrochinolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl,1,3-dioxolanyl, 1,3-dioxolenyl, 3,3-dioxo[1,3,4]oxathiazinyl,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuranyl, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isothiazolidinyl, isothiazolinyl,isoxazolyl, isoxazolinyl, isoxazol idinyl, 2-isoxazolinyl,ketopiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2-oxa-thiepanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl,1,4-oxazepinyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl,oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl,pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl,tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl,1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl,thietanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The heterocyclic rings are unsubstituted or mono-, di- or trisubstitutedby suitable groups such as, for example: F, Cl, Br, I, CF3, NO2, CN,COOH, CO—O—(C0-C4) alkylene-(C6-C10) aryl, CO—O—(C1-C4) alkyl,CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl, CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, CO—N((C0-C4)alkylene-H)—(C1-C6)alkylene-H, CO—N((C0-C4)alkylene-H)—(C1-C6)cycloalkyl, CON((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl, (C0-C4)alkylene-(C3-C6)cycloalkyl, (C3-C6)alkyl, (C2-C6)-alkenyl,(C2-C6)-alkinyl, (C0-C4) alkylene-(C6-C10)aryl, (C0-C4)alkylene-(C3-C15)heterocycle, O—(C0-C6)-alkyl, (C0-C4)alkylene-O—(C0-C4) alkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C13)cycloalkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C6-C10)aryl, (C0-C4) alkylene-O—(C0-C4)alkylene-(C3-C15)heterocycle, O—CO—O—(C0-C4) alkylene-(C6-C10) aryl,O—CO—O—(C1-C4) alkyl, O—CO—O—(C0-C4) alkylene-(C3-C13)cycloalkyl,O—CO—O—(C0-C4) alkylene-(C3-C15)heterocycle, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-(C6-C10) aryl, O—CO—N((C0-C4)alkylene-H)—(C0-C4) alkylene-H, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl, O—CO—N((C0-C4) alkylene-H)—(C0-C4)alkylene-(C3-C15) heterocycle, S—(C1-C4)alkyl, S—(C0-C4)alkylene-(C3-C13)cycloalkyl, S—(C0-C4) alkylene-(C6-C10) aryl, S—(C0-C4)alkylene-(C3-C15) heterocycle, SO—(C1-C4)alkyl, SO—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO—(C0-C4) alkylene-(C6-C10) aryl,SO—(C0-C4) alkylene-(C3-C15) heterocycle, SO2—(C1-C4)alkyl, SO2—(C0-C4)alkylene-(C3-C13)cycloalkyl, SO2—(C0-C4) alkylene-(C6-C10) aryl,SO2—(C0-C4) alkylene-(C3-C15) heterocycle,SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C10)aryl,SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-H, SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,SO2—N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, where thearyl ring or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H;N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, N((C0-C4)alkylene-H)—(C0-C4)alkylene-H)—(C1-C6)cycloalkyl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—O—(C0-C4)alkylene-(C3-C15)heterocycle, N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C6-C12)-aryl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C13)cycloalkyl,N((C0-C4)alkylene-H)—CO—N((C0-C4)-alkylene-H)—(C0-C4)alkylene-(C3-C15)heterocycle,where the aryl or heterocyclic ring is unsubstituted or mono- ordisubstituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl,(C1-C6)-alkyl, N((C0-C4)-alkylene-H)—(C0-C4)-alkylene-H, SO2—CH3, COOH,COO—(C1-C6)-alkyl, SF5, CONH2.

Halogen is fluorine, chlorine, bromine or iodine.

Optically active carbon atoms present in the compounds of the formula Ican independently of each other have R configuration or S configuration.The compounds of the formula I can be present in the form of pureenantiomers or pure diastereomers or in the form of mixtures ofenantiomers and/or diastereomers, for example in the form of racemates.The present invention relates to pure enantiomers and mixtures ofenantiomers as well as to pure diastereomers and mixtures ofdiastereomers. The invention comprises mixtures of two or of more thantwo stereoisomers of the formula I and it comprises all ratios of thestereoisomers in the mixtures. In case the compounds of the formula Ican be present as E isomers or Z isomers (or cis isomers or transisomers) the invention relates both to pure E isomers and pure Z isomersand to E/Z mixtures in all ratios. The invention also comprises alltautomeric forms of the compounds of the formula I.

Diastereomers, including E/Z isomers, can be separated into theindividual isomers, for example, by chromatography. Racemates can beseparated into the two enantiomers by customary methods, for example bychromatography on chiral phases or by resolution, for example bycrystallization of diastereomeric salts obtained with optically activeacids or bases. Stereochemically uniform compounds of the formula I canalso be obtained by employing stereochemically uniform startingmaterials or by using stereoselective reactions.

The compounds of the formula I may exist in the form of their racemates,racemic mixtures, pure enantiomers, diastereomers and mixtures ofdiastereomers as well in their tautomeric forms. The present inventionencompasses all these isomeric and tautomeric forms of the compounds ofthe formula I. These isomeric forms can be obtained by known methodseven if not specifically described in some cases.

Pharmaceutically acceptable salts are, because their solubility in wateris greater than that of the initial or basic compounds, particularlysuitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acid, and of organicacids such as, for example, acetic acid, benzenesulfonic, benzoic,citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts),alkaline earth metal salts (such as magnesium and calcium salts), andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion such as, for example,trifluoroacetate likewise belong within the framework of the inventionas useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

The term “physiologically functional derivative” used herein refers toany physiologically tolerated derivative of a compound of the formula Iof the invention, for example an ester, which on administration to amammal such as, for example, a human is able to form (directly orindirectly) a compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives also include prodrugs of thecompounds of the invention, as described, for example, in H. Okada etal., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can bemetabolized in vivo to a compound of the invention. These prodrugs maythemselves be active or not.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and their salts,solvates and physiologically functional derivatives as described herein.

Use

This invention relates further to the use of compounds of the formula Iand their pharmaceutical compositions as PPAR ligands. The PPAR ligandsof the invention are suitable as modulators of PPAR activity.

Peroxisome proliferator-activated receptors (PPAR) are transcriptionfactors which can be activated by ligands and belong to the class ofnuclear hormone receptors. There are three PPAR isoforms, PPARalpha,PPARgamma and PPARdelta (identical to PPARbeta), which are encoded bydifferent genes (Peroxisome proliferator-activated receptor (PPAR):structure, mechanisms of activation and diverse functions: Motojima K.,Cell Struct Funct., 1993,18(5), 267-77).

In humans, PPARgamma exists in three variants, PPARgamma₁, gamma₂, andgamma₃, which are the result of alternative use of promoters anddifferential mRNA splicing. Different PPARs have different tissuedistribution and modulate different physiological functions. The PPARsplay a key role in various aspects of the regulation of a large numberof genes, the products of which genes are directly or indirectlycrucially involved in lipid and carbohydrate metabolism. Thus, forexample, the PPARalpha receptor plays an important part in theregulation of fatty acid catabolism or lipoprotein metabolism in theliver, while PPARgamma is crucially involved for example in regulatingadipose cell differentiation. In addition, however, PPARs are alsoinvolved in the regulation of many other physiological processes,including those which are not directly connected with carbohydrate orlipid metabolism. The activity of different PPARs can be modulated byvarious fatty acids, fatty acid derivatives and synthetic compounds tovarying extents. For relevant reviews about functions, physiologicaleffects and pathophysiology, see: Berger, J. et al., Annu. Rev. Med.,2002, 53, 409-435; Wilson, T. et al., J. Med. Chem., 2000, 43 (4),527-550; Kliewer, S. et al., Recent Prog Horm Res., 2001, 56, 239-63;Moller, D. E. and Berger, J. P., Int J Obes Relat Metab Disord., 2003,27 Suppl 3, 17-21; Ram, V. J., Drugs Today, 2003, 39(8), 609-32).

Among the three PPAR-isoforms the physiological functions of PPARdeltahave long remained an enigma. The first proposed pharmacological rolefor PPARdelta has been the regulation of cholesterol homeostasis. It wasshown that the somewhat selective PPARdelta ligand L-165041 raisesplasma cholesterol in a diabetic animal model (Berger J. et al., J.Biol. Chem., 1999, 274, 6718-6725; Leibowitz M. D. et al., FEBS Lett.,2000, 473(3), 333-336). In obese, insulin resistant rhesus monkeys, thepotent and selective PPARdelta ligand GW501516 raises HDL-cholesterol,decreases plasma LDL-cholesterol, triglycerides and insulin levels(Oliver, W. et al., Proc. Natl. Acad. Sci., 2001, 98, 5306-5311). Thedual PPARdelta/PPARalpha agonist YM-16638 significantly lowers plasmalipids in rhesus and cynomolgus monkeys (Goto, S. et al., Br. J. Pharm.,1996, 118, 174-178) and acts in a similar manner in two weeks clinicaltrials in healthy volunteers (Shimokawa, T. et al., Drug Dev. Res.,1996, 38, 86-92). More recent publications underline that PPARdelta isan important target for the treatment of dyslipidemia, insulinresistance, type 2 diabetes, atherosclerosis and syndrom X (Wang, Y-X.et al., Cell, 2003, 113, 159-170; Luquet, S. et al., FASEB J., 2003, 17,209-226; Tanaka, T. et al., PNAS, 2003, 100, 15924-15929; Holst, D. etal., BioChem. Biophys. Acta, 2003, 1633, 43-50; Dressel, U. et al., Mol.Endocrin., 2003, 17, 2477-2493; Lee, C. H. et al., Science, 2003, 302,453-457).

Besides its actions as a regulator of the lipid-, glucose- andcholesterol-metabolism PPARdelta is known to play a role in embryonicdevelopment, implantation and bone formation (Lim, H. and Dey, S. K.,Trends Endocrinol Metab., 2000, 11(4), 137-42; Ding, N. Z. et al., MolReprod Dev., 2003, 66(3), 218-24; Mano, H. et al., J Biol Chem., 2000,275(11), 8126-32).

Numerous publications demonstrate that PPARdelta is triggeringproliferation and differentiation of keratinocytes which points to itsrole in skin disorders and wound healing (Di-Poi, N. et al., J SteroidBiochem Mol Biol., 2003, 85(2-5), 257-65; Tan, N. S. et al., Am J ClinDermatol., 2003, 4(8), 523-30; Wahli, W., Swiss Med. Wkly., 2002,132(7-8), 83-91).

PPARdelta appears to be significantly expressed in the CNS; however muchof its function there still remains undiscovered. Of singular interesthowever, is the discovery that PPARdelta was expressed in rodentoligodendrocytes, the major lipid producing cells of the CNS (J.Granneman, et al., J. Neurosci. Res., 1998, 51, 563-573). Moreover, itwas also found that a PPARdelta selective agonist was found tosignificantly increase oligodendroglial myelin gene expression andmyelin sheath diameter in mouse cultures (I. Saluja et al., Glia, 2001,33, 194-204). Thus, PPARdelta activators may be of use for the treatmentof demyelinating and dysmyelinating diseases. The use of peroxisomeproliferator activated receptor delta agonists for the treatment of MSand other demyelinating diseases can be shown as described inWO2005/097098.

Demyelinating conditions are manifested in loss of myelin—the multipledense layers of lipids and protein which cover many nerve fibers. Theselayers are provided by oligodendroglia in the central nervous system(CNS), and Schwann cells in the peripheral nervous system (PNS). Inpatients with demyelinating conditions, demyelination may beirreversible; it is usually accompanied or followed by axonaldegeneration, and often by cellular degeneration. Demyelination canoccur as a result of neuronal damage or damage to the myelinitself—whether due to aberrant immune responses, local injury, ischemia,metabolic disorders, toxic agents, or viral infections (Prineas andMcDonald, Demyelinating Diseases. In Greenfield's Neuropathology,6.sup.th ed. (Edward Arnold: New York, 1997) 813-811, Beers and Berkow,eds., The Merck Manual of Diagnosis and Therapy, 17.sup.th ed.(Whitehouse Station, N.J.: Merck Research Laboratories, 1999) 1299,1437, 1473-76, 1483).

Central demyelination (demyelination of the CNS) occurs in severalconditions, often of uncertain etiology, that have come to be known asthe primary demyelinating diseases. Of these, multiple sclerosis (MS) isthe most prevalent. Other primary demyelinating diseases includeadrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS-vacuolarmyelopathy, HTLV-associated myelopathy, Leber's hereditary opticatrophy, progressive multifocal leukoencephalopathy (PML), subacutesclerosing panencephalitis, Guillian-Barre syndrome and tropical spasticparaparesis. In addition, there are acute conditions in whichdemyelination can occur in the CNS, e.g., acute disseminatedencephalomyelitis (ADEM) and acute viral encephalitis. Furthermore,acute transverse myelitis, a syndrome in which an acute spinal cordtransection of unknown cause affects both gray and white matter in oneor more adjacent thoracic segments, can also result in demyelination.Also, disorders in which myelin forming glial cells are damagedincluding spinal cord injuries, neuropathies and nerve injury.

The present invention relates to compounds of the formula I suitable formodulating the activity of PPARs, especially the activity of PPARdeltaand PPARalpha. Depending on the modulation profile, the compounds of theformula I are suitable for the treatment, control and prophylaxis of theindications described hereinafter, and for a number of otherpharmaceutical applications connected thereto (see, for example, Berger,J., et al., Annu. Rev. Med., 2002, 53, 409-435; Wilson, T. et al., J.Med. Chem., 2000, 43(4), 527-550; Kliewer, S. et al., Recent Prog HormRes., 2001, 56, 239-63; Fruchart, J. C. et al., 2001, PharmacologicalResearch, 44(5), 345-52; Kersten, S. et al., Nature, 2000, 405, 421-424;Torra, I. P. et al., Curr Opin Lipidol, 2001, 12, 245-254).

Compounds of this type are particularly suitable for the treatmentand/or prevention of:

-   1. —Disorders of fatty acid metabolism and glucose utilization    disorders.    -   Disorders in which insulin resistance is involved-   2. Diabetes mellitus, especially type 2 diabetes, including the    prevention of the sequelae associated therewith.    -   Particular aspects in this connection are        -   hyperglycemia,        -   improvement in insulin resistance,        -   improvement in glucose tolerance,        -   protection of the pancreatic β cells        -   prevention of macro- and microvascular disorders-   3. Dyslipidemias and their sequelae such as, for example,    atherosclerosis, coronary heart disease, cerebrovascular disorders    etc, especially those (but not restricted thereto) which are    characterized by one or more of the following factors:    -   high plasma triglyceride concentrations, high postprandial        plasma triglyceride concentrations,    -   low HDL cholesterol concentrations    -   low ApoA lipoprotein concentrations    -   high LDL cholesterol concentrations    -   small dense LDL cholesterol particles    -   high ApoB lipoprotein concentrations-   4. Various other conditions which may be associated with the    metabolic syndrome, such as:    -   obesity (excess weight), including central obesity    -   thromboses, hypercoagulable and prothrombotic states (arterial        and venous)    -   high blood pressure    -   heart failure such as, for example (but not restricted thereto),        following myocardial infarction, hypertensive heart disease or        cardiomyopathy-   5. Disorders or conditions in which inflammatory reactions are    involved:    -   atherosclerosis such as, for example (but not restricted        thereto), coronary sclerosis including angina pectoris or        myocardial infarction, stroke    -   vascular restenosis or reocclusion    -   chronic inflammatory bowel diseases such as, for example,        Crohn's disease and ulcerative colitis    -   asthma    -   lupus erythematosus (LE) or inflammatory rheumatic disorders        such as, for example, rheumatoid arthritis    -   other inflammatory states-   6. Disorders of cell cycle or cell differentiation processes:    -   adipose cell tumors    -   lipomatous carcinomas such as, for example, liposarcomas    -   solid tumors and neoplasms such as, for example (but not        restricted thereto), carcinomas of the gastrointestinal tract,        of the liver, of the biliary tract and of the pancreas,        endocrine tumors, carcinomas of the lungs, of the kidneys and        the urinary tract, of the genital tract, prostate carcinomas etc    -   acute and chronic myeloproliferative disorders and lymphomas    -   angiogenesis-   7. Demyelinating and other neurodegenerative disorders of the    central and peripheral nervous systems including:    -   Alzheimer's disease    -   multiple sclerosis    -   Parkinson's disease    -   adrenoleukodystrophy (ALD)    -   adrenomyeloneuropathy    -   AIDS-vacuolar myelopathy    -   HTLV-associated myelopathy    -   Leber's hereditary optic atrophy    -   progressive multifocal leukoencephalopathy (PML)    -   subacute sclerosing panencephalitis    -   Guillian-Barre syndrome    -   tropical spastic paraparesis    -   acute disseminated encephalomyelitis (ADEM)    -   acute viral encephalitis    -   acute transverse myelitis    -   spinal cord and brain trauma    -   Charcot-Marie-Tooth disease-   8. Skin disorders and/or disorders of wound healing processes:    -   erythemato-squamous dermatoses such as, for example, psoriasis    -   acne vulgaris    -   other skin disorders and dermatological conditions which are        modulated by PPAR    -   eczemas and neurodermitis    -   dermatitis such as, for example, seborrheic dermatitis or        photodermatitis    -   keratitis and keratoses such as, for example, seborrheic        keratoses, senile keratoses, actinic keratosis, photo-induced        keratoses or keratosis follicularis    -   keloids and keloid prophylaxis    -   warts, including condylomata or condylomata acuminata    -   human papilloma viral (HPV) infections such as, for example,        venereal papillomata, viral warts such as, for example,        molluscum contagiosum, leukoplakia    -   papular dermatoses such as, for example, Lichen planus    -   skin cancer such as, for example, basal-cell carcinomas,        melanomas or cutaneous T-cell lymphomas    -   localized benign epidermal tumors such as, for example,        keratoderma, epidermal naevi    -   chilblains    -   wound healing-   9. Other disorders    -   high blood pressure    -   pancreatitis    -   syndrome X    -   polycystic ovary syndrome (PCOS)    -   asthma    -   osteoarthritis    -   lupus erythematosus (LE) or inflammatory rheumatic disorders        such as, for example, rheumatoid arthritis    -   vasculitis    -   wasting (cachexia)    -   gout    -   ischemia/reperfusion syndrome    -   acute respiratory distress syndrome (ARDS)

Formulations

The amount of a compound of formula I necessary to achieve the desiredbiological effect depends on a number of factors, for example thespecific compound chosen, the intended use, the mode of administrationand the clinical condition of the patient. The daily dose is generallyin the range from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg)per day and per kilogram of bodyweight, for example 0.1-10 mg/kg/day. Anintravenous dose may be, for example, in the range from 0.001 mg to 1.0mg/kg, which can suitably be administered as infusion of 10 ng to 100 ngper kilogram and per minute. Suitable infusion solutions for thesepurposes may contain, for example, from 0.1 ng to 10 mg, typically from1 ng to 10 mg, per milliliter. Single doses may contain, for example,from 1 mg to 10 g of the active ingredient. Thus, ampules for injectionsmay contain, for example, from 1 mg to 100 mg, and single-doseformulations which can be administered orally, such as, for example,capsules or tablets, may contain, for example, from 0.05 to 1000 mg,typically from 0.5 to 600 mg. For the therapy of the abovementionedconditions, the compounds of formula I may be used as the compounditself, but they are preferably in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier must, of course, beacceptable in the sense that it is compatible with the other ingredientsof the composition and is not harmful for the patient's health. Thecarrier may be a solid or a liquid or both and is preferably formulatedwith the compound as a single dose, for example as a tablet, which maycontain from 0.05% to 95% by weight of the active ingredient. Otherpharmaceutically active substances may likewise be present, includingother compounds of formula I. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingredients withpharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical preparations for oral administration may be inthe form of separate units such as, for example, capsules, cachets,suckable tablets or tablets, each of which contain a defined amount ofthe compound of formula I; as powders or granules, as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. The compositionsare generally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surface-active/dispersing agent(s) in a suitable machine.

Molded tablets can be produced by molding the compound, which is inpowder form and is moistened with an inert liquid diluent, in a suitablemachine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula I with a flavoring, normally sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula I, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of from0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single plasterswhich are suitable for long-term close contact with the patient'sepidermis. Such plasters suitably contain the active ingredient in anaqueous solution which is buffered where appropriate, dissolved and/ordispersed in an adhesive or dispersed in a polymer. A suitable activeingredient concentration is about 1% to 35%, preferably about 3% to 15%.A particular possibility is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

The compounds of the formula I are distinguished by favorable effects onmetabolic disorders. They beneficially influence lipid and sugarmetabolism, in particular they lower the triglyceride level and aresuitable for the prevention and treatment of type II diabetes andatheriosclerosis and the diverse sequalae thereof.

Combinations with Other Medicaments

The compounds of the invention can be administered alone or incombination with one or more further pharmacologically activesubstances. In particular, the compounds of the invention can beadministered in combination with active ingredients having a similarpharmacological action. For example, they can be administered incombination with active ingredients which have favorable effects onmetabolic disturbances or disorders frequently associated therewith.Examples of such medicaments are

-   -   1. medicaments which lower blood glucose, antidiabetics,    -   2. active ingredients for the treatment of dyslipidemias,    -   3. antiatherosclerotic medicaments,    -   4. antiobesity agents,    -   5. antiinflammatory active ingredients    -   6. active ingredients for the treatment of malignant tumors    -   7. antithrombotic active ingredients    -   8. active ingredients for the treatment of high blood pressure    -   9. active ingredients for the treatment of heart failure and    -   10. active ingredients for the treatment and/or prevention of        complications caused by diabetes or associated with diabetes.    -   11. active ingredients for the treatment of neurodegenerative        diseases    -   12. active ingredients for the treatment of disorders of the        central nervous system    -   13. active ingredients for the treatment of drug, nicotine and        alcohol addiction    -   14. analgesics

They can be combined with the compounds of the invention of the formulaI in particular for a synergistic enhancement of activity.Administration of the active ingredient combination can take placeeither by separate administration of the active ingredients to thepatient or in the form of combination products in which a plurality ofactive ingredients are present in one pharmaceutical preparation.

Further active ingredients suitable for combination products are:

All antidiabetics which are mentioned in the Rote Liste 2005, chapter12; all weight-reducing agents/appetite suppressants which are mentionedin the Rote Liste 2005, chapter 1; all lipid-lowering agents which arementioned in the Rote Liste 2005, chapter 58. They may be combined withthe compound of the invention of the formula I in particular for asynergistic improvement in the effect. The active ingredient combinationcan be administered either by separate administration of the activeingredients to the patient or in the form of combination products inwhich a plurality of active ingredients is present in a pharmaceuticalpreparation. Most of the active ingredients mentioned hereinafter aredisclosed in the USP Dictionary of USAN and International Drug Names, USPharmacopeia, Rockville 2001.

Antidiabetics include insulin and insulin derivatives such as, forexample, Lantus® (see www.lantus.com) or HMR 1964 or Levemir® (insulindetemir) or those described in WO2005005477 (Novo Nordisk), fast-actinginsulins (see U.S. Pat. No. 6,221,633), inhalable insulins such as, forexample, Exubera® or oral insulins such as, for example, IN-105 (Nobex)or Oral-lyn™ (Generex Biotechnology), GLP-1 derivatives and GLP-1agonists such as, for example, exenatide, liraglutide or those whichhave been disclosed in WO98/08871, WO2005027978, WO2006037811 orWO2006037810 of Novo Nordisk A/S, in WO01/04156 of Zealand or inWO0/34331 of Beaufour-lpsen, pramlintide acetate (Symlin; AmylinPharmaceuticals), BIM-51077, PC-DAC-exendin-4 (an exendin-4 analogcovalently bonded to recombinant human albumin), agonists like thosedescribed for example in D. Chen et al., Proc. Natl. Acad. Sci. USA 104(2007) 943, those as are described in WO2006124529, and orally effectivehypoglycemic active ingredients.

Antidiabetics also include agonists of the glucose-dependentinsulinotropic polypeptide (GIP) receptor as are described for examplein WO2006121860.

The orally effective hypoglycemic active ingredients include preferably

sulfonylureas,biguanidines,meglitinides,oxadiazolidinediones,thiazolidinediones,glucosidase inhibitors,inhibitors of glycogen phosphorylase,glucagon antagonists,glucokinase activators,inhibitors of fructose-1,6-bisphosphatase,modulators of glucose transporter 4 (GLUT4),inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT),GLP-1 agonists,potassium channel openers such as, for example, pinacidil, cromakalim,diazoxide or those described in R. D. Carr et al., Diabetes 52, 2003,2513.2518, in J. B. Hansen et al., Current Medicinal Chemistry 11, 2004,1595-1615, in T. M. Tagmose et al., J. Med. Chem. 47, 2004, 3202-3211 orin M. J. Coghlan et al., J. Med. Chem. 44, 2001, 1627-1653, or thosewhich have been disclosed in WO 97/26265 and WO 99/03861 of Novo NordiskA/S,inhibitors of dipeptidylpeptidase IV (DPP-IV),insulin sensitizers,inhibitors of liver enzymes involved in stimulating gluconeogenesisand/or glycogenolysis,modulators of glucose uptake, of glucose transport and of glucosereabsorption,inhibitors of 11β-HSD1,inhibitors of protein tyrosine phosphatase 1B (PTP1B),modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1,SGLT2),compounds which alter lipid metabolism such as antihyperlipidemic activeingredients and antilipidemic active ingredients,compounds which reduce food intake,compounds which increase thermogenesis,PPAR and RXR modulators andactive ingredients which act on the ATP-dependent potassium channel ofthe beta cells.

In one embodiment of the invention, the compounds of the formula I isadministered in combination with an HMGCOA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin or L-659699.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a cholesterol absorption inhibitor suchas, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4(sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech,WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497,WO2005021495) or with compounds as described in WO2002066464,WO2005000353 (Kotobuki Pharmaceutical Co. Ltd.), or WO2005044256 orWO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZenecaAB), and WO2006017257 (Phenomix) or WO2005033100 (Lipideon BiotechnologyAG), or as described in WO2004097655, WO2004000805, WO2004000804,WO2004000803, WO2002050068, WO2002050060, WO2005047248, WO2006086562,WO2006102674, WO2006116499, WO2006121861, WO2006122186, WO2006122216,WO2006127893, WO2006137794, WO2006137796, WO2006137782, WO2006137793,WO2006137797, WO2006137795, WO2006137792, WO2006138163.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Vytorin™, a fixed combination ofezetimibe and simvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fixed combination of ezetimibe withatorvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fixed combination of ezetimibe withfenofibrate.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a fixed combination of fenofibrateand rosuvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Synordia®, a fixed combination offenofibrate with metformin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with ISIS-301012, an antisenseoligonucleotide able to regulate the apolipoprotein B gene.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR gamma agonist such as, forexample, rosiglitazone, pioglitazone, JTT-501, GI 262570, R-483, CS-011(rivoglitazone).

In one embodiment of the invention, the compound of the formula I isadministered in combination with Competact™, a fixed combination ofpioglitazone hydrochloride with metformin hydrochloride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Tandemact™, a fixed combination ofpioglitazone with glimepiride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fixed combination of pioglitazonehydrochloride with an angiotensin II agonist such as, for example,TAK-536.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR alpha agonist such as, forexample, GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945, LY-518674or those as are described in WO2001040207, WO2002096894, WO2005097076.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a mixed PPAR alpha/gamma agonist suchas, for example, naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042,AVE 8134, AVE 0847, CKD-501 (lobeglitazone sulfate) or as described inWO 00/64888, WO 00/64876, WO03/020269 or in J. P. Berger et al., TRENDSin Pharmacological Sciences 28(5), 244-251, 2005.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR delta agonist such as, forexample, GW-501516 or as described in WO2006059744, WO2006084176,WO2006029699, WO2007039172-WO2007039178.

In one embodiment, the compound of the formula I is administered incombination with metaglidasen or with MBX-2044 or other partial PPARgamma agonists/antagonists.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fibrate such as, for example,fenofibrate, clofibrate or bezafibrate.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an MTP inhibitor such as, for example,implitapide, BMS-201038, R-103757, AS-1552133 or those described inWO2005085226, WO2005121091, WO2006010423.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a CETP inhibitor such as, for example,torcetrapib or JTT-705 or those described in WO2006002342, WO2006010422,WO2006012093, WO2006073973, WO2006072362, WO2006097169, WO2007041494.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a bile acid absorption inhibitor (see,for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 orWO00/61568), such as, for example, HMR 1741 or those as described in DE10 2005 033099.1 and DE 10 2005 033100.9, WO2007009655-56.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a polymeric bile acid adsorbent suchas, for example, cholestyramine or colesevelam.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512), such as, for example, HMR1171, HMR1586 or those asdescribed in WO2005097738.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ABCA1 expression enhancer asdescribed for example in WO2006072393.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with an RNAi therapeutic directed againstPCSK9 (proprotein convertase subtilisin/kexin type 9).

In one embodiment, the compound of the formula I is administered incombination with Omacor® (omega-3 fatty acids; highly concentrated ethylesters of eicosapentaenoic acid and of docosahexaenoic acid).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ACAT inhibitor such as, for example,avasimibe or SMP-797.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an antioxidant such as, for example,OPC-14117, probucol, tocopherol, ascorbic acid, β-carotene or selenium.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a vitamin such as, for example, vitaminB6 or vitamin B12.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein lipase modulator such as,for example, ibrolipim (NO-1886).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ATP citrate lyase inhibitor such as,for example, SB-204990.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a squalene synthetase inhibitor suchas, for example, BMS-188494, TAK-475 or as described in WO2005077907,JP2007022943.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein (a) antagonist such as,for example, gemcabene (CI-1027).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR109A (HM74A receptoragonist; NAR agonist (nicotinic acid receptor agonist) such as, forexample, nicotinic acid or extended release niacin in conjunction withMK-0524A or those compounds described in WO2006045565, WO2006045564,WO2006069242, WO2006124490, WO2006113150, WO2007017261, WO2007017262,WO2007017265, WO2007015744, WO2007027532.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR116 as are describedfor example in WO2006067531, WO2006067532.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipase inhibitor such as, forexample, orlistat or cetilistat (ATL-962).

In one embodiment of the invention, the compound of the formula I isadministered in combination with insulin.

In one embodiment, the compound of the formula I is administered incombination with a sulfonylurea such as, for example, tolbutamide,glibenclamide, glipizide, gliclazide or glimepiride.

In one embodiment, the compound of the formula I is administered incombination with a substance which enhances insulin secretion, such as,for example, KCP-265 (WO2003097064) or those described in WO2007026761.

In one embodiment, the compound of the formula I is administered incombination with agonists of the glucose-dependent insulinotropicreceptor (GDIR) such as, for example, APD-668.

In one embodiment, the compound of the formula I is administered incombination with a biguanide such as, for example, metformin.

In yet another embodiment, the compound of the formula I is administeredin combination with a meglitinide such as, for example, repaglinide,nateglinide or mitiglinide.

In a further embodiment, the compound of the formula I is administeredwith a combination of mitiglinide with a glitazone, e.g. pioglitazonehydrochloride.

In a further embodiment, the compound of the formula I is administeredwith a combination of mitiglinide with an alpha-glucosidase inhibitor.

In one embodiment, the compound of the formula I is administered incombination with a thiazolidinedione such as, for example, troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 of Dr. Reddy's Research Foundation, in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]-phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compound of the formula I is administered incombination with an α-glucosidase inhibitor such as, for example,miglitol or acarbose.

In one embodiment, the compound of the formula I is administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, such as, for example, tolbutamide,glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compound of the formula I is administered incombination with more than one of the aforementioned compounds, e.g. incombination with a sulfonylurea and metformin, a sulfonylurea andacarbose, repaglinide and metformin, insulin and a sulfonylurea, insulinand metformin, insulin and troglitazone, insulin and lovastatin, etc.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen phosphorylase, such as, forexample, PSN-357 or FR-258900 or those as described in WO2003084922,WO2004007455, WO2005073229-31 or WO2005067932.

In one embodiment, the compound of the formula I is administered incombination with glucagon receptor antagonists such as, for example,A-770077, NNC-25-2504 or as described in WO2004100875 or WO2005065680.

In one embodiment, the compound of the formula I is administered incombination with activators of glucokinase, such as, for example,LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50 or those as aredescribed for example in WO2004072031, WO2004072066, WO2005080360,WO2005044801, WO2006016194, WO2006058923, WO2006112549, WO2006125972,WO2007017549, WO2007017649, WO2007007910, WO2007007040-42,WO2007006760-61, WO2007006814, WO2007007886, WO2007028135, WO2007031739,WO2007041365, WO2007041366, WO2007037534, WO2007043638, WO2007053345,WO2007051846, WO2007051845, WO2007053765, WO2007051847.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of gluconeogenesis, such as, for example,FR-225654.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of fructose-1,6-bisphosphatase (FBPase),such as, for example, CS-917 (MB-06322) or MB-07803 or those describedin WO2006023515, WO2006104030, WO2007014619.

In one embodiment, the compound of the formula I is administered incombination with modulators of glucose transporter 4 (GLUT4), such as,for example, KST-48 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54(12), 835 (2004)).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of glutamine-fructose-6-phosphateamidotransferase (GFAT), as are described for example in WO2004101528.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of dipeptidylpeptidase IV (DPP-IV), such as,for example, vildagliptin (LAF-237), sitagliptin (MK-0431), sitagliptinphosphate, saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322,SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X, KRP-104, DP-893,ABT-341, ABT-279 or another salt thereof or those compounds as aredescribed in WO2003074500, WO2003106456, WO2004037169, WO200450658,WO2005058901, WO2005012312, WO2005/012308, WO2006039325, WO2006058064,WO2006015691, WO2006015701, WO2006015699, WO2006015700, WO2006018117,WO2006099943, WO2006099941, JP2006160733, WO2006071752, WO2006065826,WO2006078676, WO2006073167, WO2006068163, WO2006090915, WO2006104356,WO2006127530, WO2006111261, WO2007015767, WO2007024993, WO2007029086.

In one embodiment, the compound of the formula I is administered incombination with Janumet™, a fixed combination of sitagliptin phosphatewith metformin hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of 11-beta-hydroxysteroid dehydrogenase 1(11β-HSD1), such as, for example, BVT-2733, JNJ-25918646, INCB-13739 orthose as are described for example in WO200190090-94, WO200343999,WO2004112782, WO200344000, WO200344009, WO2004112779, WO2004113310,WO2004103980, WO2004112784, WO2003065983, WO2003104207, WO2003104208,WO2004106294, WO2004011410, WO2004033427, WO2004041264, WO2004037251,WO2004056744, WO2004058730, WO2004065351, WO2004089367, WO2004089380,WO2004089470-71, WO2004089896, WO2005016877, WO2005097759, WO2006010546,WO2006012227, WO2006012173, WO2006017542, WO2006034804, WO2006040329,WO2006051662, WO2006048750, WO2006049952, WO2006048331, WO2006050908,WO2006024627, WO2006040329, WO2006066109, WO2006074244, WO2006078006,WO2006106423, WO2006132436, WO2006134481, WO2006134467, WO2006135795,WO2006136502, WO2006138695, WO2006133926, WO2007003521, WO2007007688,US2007066584, WO2007047625, WO2007051811, WO2007051810.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of protein tyrosine phosphatase 1B (PTP1B),as are described for example in WO200119830-31, WO200117516,WO2004506446, WO2005012295, WO2005116003, WO2005116003, WO2006007959, DE10 2004 060542.4, WO2007009911, WO2007028145, WO2007081755.

In one embodiment, the compound of the formula I is administered incombination with modulators of the sodium-dependent glucose transporter1 or 2 (SGLT1, SGLT2), such as, for example, KGA-2727, T-1095, SGL-0010,AVE 2268, SAR 7226 and sergliflozin or as described for example inWO2004007517, WO200452903, WO200452902, PCT/EP2005/005959, WO2005085237,JP2004359630, WO2005121161, WO2006018150, WO2006035796, WO2006062224,WO2006058597, WO2006073197, WO2006080577, WO2006087997, WO2006108842,WO2007000445, WO2007014895, WO2007080170 or by A. L. Handlon in ExpertOpin. Ther. Patents (2005) 15(11), 1531-1540.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR40 as are described for example inWO2007013689, WO2007033002.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR119b as are described for example inWO2004041274.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR119 as are described for example inWO2005061489 (PSN-632408), WO2004065380, WO2007003960-62 andWO2007003964.

In a further embodiment, the compound of the formula I is administeredin combination with modulators of GPR120.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of hormone-sensitive lipase (HSL) and/orphospholipases as described for example in WO2005073199, WO2006074957,WO2006087309, WO2006111321, WO2007042178.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of acetyl-CoA carboxylase (ACC), such as,for example, those as described in WO199946262, WO200372197,WO2003072197, WO2005044814, WO2005108370, JP2006131559, WO2007011809,WO2007011811, WO2007013691.

In a further embodiment, the compound of the formula I is administeredin combination with modulators of xanthine oxidoreductase (XOR).

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of phosphoenolpyruvate carboxykinase(PEPCK), such as, for example, those as described in WO2004074288.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen synthase kinase 3 beta (GSK-3beta), as described for example in US2005222220, WO2005085230,WO2005111018, WO2003078403, WO2004022544, WO2003106410, WO2005058908,US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343,EP1460075, WO2004014910, WO2003076442, WO2005087727 or WO2004046117.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of the serum/glucocorticoid-regulatedkinase (SGK) as described for example in WO2006072354.

In one embodiment, the compound of the formula I is administered incombination with an agonist of the RUP3 receptor as described forexample in WO2007035355.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of protein kinase C beta (PKC beta), suchas, for example, ruboxistaurin.

In another embodiment, the compound of the formula I is administered incombination with an activator of the gene which codes for the ataxiatelangiectasia mutated (ATM) protein kinase, such as, for example,chloroquine.

In one embodiment, the compound of the formula I is administered incombination with an endothelin A receptor antagonist such as, forexample, avosentan (SPP-301).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of “I-kappaB kinase” (IKK inhibitors), asare described for example in WO2001000610, WO2001030774, WO2004022553 orWO2005097129.

In one embodiment, the compound of the formula I is administered incombination with modulators of the glucocorticoid receptor (GR), as aredescribed for example in WO2005090336, WO2006071609, WO2006135826.

In a further embodiment, the compound of the formula I is administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A. et al.: Hormone and Metabolic Research (2001), 33(9),554-558);

NPY antagonists such as, for example, naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amidehydrochloride (CGP 71683A);NPY-5 receptor antagonists such as L-152804, or as are described forexample in WO2006001318;NPY-4 receptor antagonists as are for example described in WO2007038942;NPY-2 receptor antagonists as are for example described in WO2007038943;Peptide YY 3-36 (PYY3-36) or analogous compounds, such as, for example,CJC-1682 (PYY3-36 conjugated with human serum albumin via Cys34),CJC-1643 (derivative of PYY3-36 which conjugates in vivo to serumalbumin) or those as are described in WO2005080424, WO2006095166;derivatives of the peptide obestatin as are described in WO2006096847;

CB1R (cannabinoid receptor 1) antagonists (such as, for example,rimonabant, SR147778, SLV-319, AVE-1625, MK-0364 or salts thereof orthose compounds as are described for example in EP 0656354, WO00/15609,WO2001/64632-64634, WO 02/076949, WO2005080345, WO2005080328,WO2005080343, WO2005075450, WO2005080357, WO200170700, WO2003026647-48,WO200302776, WO2003040107, WO2003007887, WO2003027069, U.S. Pat. No.6,509,367, WO200132663, WO2003086288, WO2003087037, WO2004048317,WO2004058145, WO2003084930, WO2003084943, WO2004058744, WO2004013120,WO2004029204, WO2004035566, WO2004058249, WO2004058255, WO2004058727,WO2004069838, US20040214837, US20040214855, US20040214856, WO2004096209,WO2004096763, WO2004096794, WO2005000809, WO2004099157, US20040266845,WO2004110453, WO2004108728, WO2004000817, WO2005000820, US20050009870,WO200500974, WO2004111033-34, WO200411038-39, WO2005016286,WO2005007111, WO2005007628, US20050054679, WO2005027837, WO2005028456,WO2005063761-62, WO2005061509, WO2005077897, WO2006047516, WO2006060461,WO2006067428, WO2006067443, WO2006087480, WO2006087476, WO2006100208,WO2006106054, WO2006111849, WO2006113704, WO2007009705, WO2007017124,WO2007017126, WO2007018459, WO2007016460, WO2007020502, WO2007026215,WO2007028849, WO2007031720, WO2007031721, WO2007036945, WO2007038045,WO2007039740, US20070015810, WO2007046548, WO2007047737, WO2007084319,WO2007084450);

cannabinoid receptor 1/cannabinoid receptor 2 (CB1/CB2) modulatingcompounds as described for example in WO2007001939, WO2007044215,WO2007047737;MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylicacid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]amide;(WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764,CHIR-785, PT-141 or those that are described in WO2005060985,WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720,US20050124652, WO2005051391, WO2004112793, WOUS20050222014,US20050176728, US20050164914, US20050124636, US20050130988,US20040167201, WO2004005324, WO2004037797, WO2005042516, WO2005040109,WO2005030797, US20040224901, WO200501921, WO200509184, WO2005000339,EP1460069, WO2005047253, WO2005047251, WO2005118573, EP1538159,WO2004072076, WO2004072077, WO2006021655-57, WO2007009894, WO2007015162,WO2007041061, WO2007041052;orexin receptor antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride(SB-334867-A) or those as are described for example in WO200196302,WO200185693, WO2004085403, WO2005075458 or WO2006067224);

histamine H3 receptor agonists (e.g.3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208) or those as are described in WO200064884,WO2005082893, WO2006107661, WO2007003804, WO2007016496, WO2007020213);

histamine H1/histamine H3 modulators such as for example betahistine andits dihydrochloride;CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585));CRF BP antagonists (e.g. urocortin);urocortin agonists;agonists of the beta-3 adrenoceptor such as, for example,1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanolhydrochloride (WO 01/83451); or Solabegron (GW-427353) or N-5984(KRP-204) or those described in JP2006111553, WO2002038543,WO2007048840-843;MSH (melanocyte-stimulating hormone) agonists;MCH (melanin-concentrating hormone) receptor antagonists (such as, forexample, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71,GW-803430 or compounds such as are described in WO2005085200,WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025,WO2005070898, WO2005070925, WO2004039780, WO2004092181, WO2003033476,WO2002006245, WO2002089729, WO2002002744, WO2003004027, FR2868780,WO2006010446, WO2006038680, WO2006044293, WO2006044174, JP2006176443,WO2006018280, WO2006018279, WO2006118320, WO2006130075, WO2007018248,WO2007012661, WO2007029847, WO2007024004, WO2007039462, WO2007042660,WO2007042668, WO2007042669, US2007093508, US2007093509, WO2007048802,JP2007091649);CCK-A agonists (such as, for example,{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525), SR-146131 (WO 0244150) orSSR-125180 or those as are described in WO2005116034);serotonin reuptake inhibitors (e.g. dexfenfluramine);mixed serotonin/dopamine reuptake inhibitors (e.g. bupropion) or fixedcombinations of bupropion with naltrexone;mixed sertoninergic and noradrenergic compounds (e.g. WO 00/71549);5-HT receptor agonists, e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalicacid salt (WO 01/09111);mixed dopamine/norepinephrine/acetylcholine reuptake inhibitors (e.g.tesofensine);5-HT2C receptor agonists (such as, for example, lorcaserin hydrochloride(APD-356), BVT-933 or those as are described in WO200077010,WO20077001-02, WO2005019180, WO2003064423, WO200242304, WO2005035533,WO2005082859, WO2006077025, WO2006103511);5-HT6 receptor antagonists such as for example E-6837 or BVT-74316 orthose as are described for example in WO2005058858, WO2007054257;bombesin receptor agonists (BRS-3 agonists);galanin receptor antagonists;growth hormone (e.g. human growth hormone or AOD-9604);growth hormone-releasing compounds (tertiary butyl6-benzyloxy-1-(2-diisopropyl-aminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(WO 01/85695));growth hormone secretagogue receptor antagonists (ghrelin antagonists)such as, for example, A-778193 or those as are described inWO2005030734;TRH agonists (see, for example, EP 0 462 884);uncoupling protein 2 or 3 modulators;leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.;Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881);DA agonists (bromocriptine or Doprexin);lipase/amylase inhibitors (for example WO 00/40569);inhibitors of diacylglycerol O-acyltransferases (DGATs) such as, forexample, BAY-74-4113 or as described for example in US2004/0224997,WO2004094618, WO200058491, WO2005044250, WO2005072740, JP2005206492,WO2005013907, WO2006004200, WO2006019020, WO2006064189, WO2006082952,WO2006120125, WO2006113919, WO2006134317, WO2007016538;inhibitors of fatty acid synthase (FAS) such as, for example, C75 orthose as described in WO2004005277;inhibitors of stearoyl-CoA delta9 desaturase (SCD1) as described forexample in WO2007009236, WO2007044085, WO2007046867, WO2007046868,WO20070501124;oxyntomodulin;oleoyl-estroneor thyroid hormone receptor agonists or partial agonists such as, forexample: KB-2115 or those as described in WO20058279, WO200172692,WO200194293, WO2003084915, WO2004018421, WO2005092316, WO2007003419,WO2007009913, WO2007039125.

In one embodiment, the further active ingredient is vareniclinetartrate, a partial agonist of the alpha 4-beta 2 nicotinicacetylcholine receptor.

In one embodiment, the further active ingredient is trodusquemine.

In one embodiment, the further active ingredient is a modulator of theSIRT1 enzyme.

In one embodiment of the invention, the further active ingredient isleptin; see, for example, “Perspectives in the therapeutic use ofleptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, ExpertOpinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment, the further active ingredient is dexamphetamine oramphetamine.

In one embodiment, the further active ingredient is fenfluramine ordexfenfluramine.

In another embodiment, the further active ingredient is sibutramine.

In one embodiment, the further active ingredient is mazindole orphentermine.

In one embodiment, the compound of the formula I is administered incombination with bulking agents, preferably insoluble bulking agents(see, for example, Carob/Caromax® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6). Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Höchst, 65926 Frankfurt/Main). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®. Caromax® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

It will be understood that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more further pharmacologically active substances willbe regarded as falling within the protection conferred by the presentinvention.

The activity of the compounds was tested as follows:

Determination of EC50 values of PPAR agonists in the cellular PPARalphaassay

Principle

The potency of substances which bind to human PPARalpha and activate itin an agonistic manner is analyzed using a stably transfected HEK cellline (HEK=human embryo kidney) which is referred to here as PPARalphareporter cell line. It contains two genetic elements, a luciferasereporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARalpha fusion protein(GR-GAL4-humanPPARalpha-LBD) which mediates expression of the luciferasereporter element depending on a PPARalpha ligand. The stably andconstitutively expressed fusion protein GR-GAL4-humanPPARalpha-LBD bindsin the cell nucleus of the PPARalpha reporter cell line via the GAL4protein portion to the GAL4 DNA binding motifs 5′-upstream of theluciferase reporter element which is stably integrated in the genome ofthe cell line. There is only weak expression of the luciferase reportergene in the absence of a PPARalpha ligand if fatty acid-depleted fetalcalf serum (cs-FCS) is used in the assay. PPARalpha ligands bind andactivate the PPARalpha fusion protein and thereby stimulate theexpression of the luciferase reporter gene. The luciferase which isformed can be detected by means of chemiluminescence via an appropriatesubstrate.

Construction of the PPARalpha Reporter Cell Line

The PPARalpha reporter cell line was prepared in two stages. Firstly,the luciferase reporter element was constructed and stably transfectedinto HEK cells. For this purpose, five binding sites of the yeasttranscription factor GAL4 (Accession # AF264724) were cloned in5′-upstream of a 68 bp-long minimal MMTV promoter (Accession # V01175).The minimal MMTV promoter section contains a CCAAT box and a TATAelement in order to enable efficient transcription by RNA polymerase II.The cloning and sequencing of the GAL4-MMTV construct took place inanalogy to the description of Sambrook J. et. al. (Molecular cloning,Cold Spring Harbor Laboratory Press, 1989). Then the complete Photinuspyralis gene (Accession # M15077) was cloned in 3′-downstream of theGAL4-MMTV element. After sequencing, the luciferase reporter elementconsisting of five GAL4 binding sites, MMTV promoter and luciferase genewas recloned into a plasmid which confers zeocin resistance in order toobtain the plasmid pdeltaM-GAL4-Luc-Zeo. This vector was transfectedinto HEK cells in accordance with the statements in Ausubel, F. M. etal. (Current protocols in molecular biology, Vol. 1-3, John Wiley &Sons, Inc., 1995). Then zeocin-containing medium (0.5 mg/ml) was used toselect a suitable stable cell clone which showed very low basalexpression of the luceriferase gene.

In a second step, the PPARalpha fusion protein(GR-GAL4-humanPPARalpha-LBD was introduced into the stable cell clonedescribed. For this purpose, initially the cDNA coding for theN-terminal 76 amino acids of the glucocorticoid receptor (Accession #P04150) was linked to the cDNA section coding for amino acids 1-147 ofthe yeast transcription factor GAL4 (Accession # P04386). The cDNA ofthe ligand-binding domain of the human PPARalpha receptor (amino acidsS167-Y468; Accession # S74349) was cloned in at the 3′-end of thisGR-GAL4 construct. The fusion construct prepared in this way(GR-GAL4-humanPPARalpha-LBD) was recloned into the plasmid pcDNA3(Invitrogen) in order to enable constitutive expression therein by thecytomegalovirus promoter. This plasmid was linearized with a restrictionendonuclease and stably transfected into the previously described cellclone containing the luciferase reporter element. The finished PPARalphareporter cell line which contains a luciferase reporter element andconstitutively expresses the PPARalpha fusion protein (GR-GAL4-humanPPARalpha-LBD) was isolated by selection with zeocin (0.5 mg/ml) andG418 (0.5 mg/ml).

Assay Procedure

The activity of PPARalpha agonists is determined in a 3-day assay whichis described below:

Day 1

The PPARalphareporter cell line is cultivated to 80% confluence in DMEM(# 41965-039, Invitrogen) which is mixed with the following additions:10% cs-FCS (fetal calf serum; #SH-30068.03, Hyclone), 0.5 mg/ml zeocin(#R250-01, Invitrogen), 0.5 mg/ml G418 (#10131-027, Invitrogen), 1%penicillin-streptomycin solution (#15140-122, Invitrogen) and 2 mML-glutamine (#25030-024, Invitrogen). The cultivation takes place instandard cell culture bottles (# 353112, Becton Dickinson) in a cellculture incubator at 37° C. in the presence of 5% CO₂. The 80%-confluentcells are washed once with 15 ml of PBS (#14190-094, Invitrogen),treated with 3 ml of trypsin solution (#25300-054, Invitrogen) at 37° C.for 2 min, taken up in 5 ml of the DMEM described and counted in a cellcounter. After dilution to 500.000 cells/ml, 35,000 cells are seeded ineach well of a 96 well microtiter plate with a clear plastic base(#3610, Corning Costar). The plates are incubated in the cell cultureincubator at 37° C. and 5% CO₂ for 24 h.

Day 2

PPARalpha agonists to be tested are dissolved in DMSO in a concentrationof 10 mM. This stock solution is diluted in DMEM (#41965-039,Invitrogen) which is mixed with 5% cs-FCS (#SH-30068.03, Hyclone), 2 mML-glutamine (#25030-024, Invitrogen) and the previously describedantibiotics (zeocin, G418, penicillin and streptomycin).

Test substances are tested in 11 different concentrations in the rangefrom 10 μM to 100 pM. More potent compounds are tested in concentrationranges from 1 μM to 10 pM or between 100 nM and 1 pM.

The medium of the PPARalpha reporter cell line seeded on day 1 iscompletely removed by aspiration, and the test substances diluted inmedium are immediately added to the cells. The dilution and addition ofthe substances is carried out by a robot (Beckman FX). The final volumeof the test substances diluted in medium is 100 μl per well of a 96 wellmicrotiter plate. The DMSO concentration in the assay is less than 0.1%v/v in order to avoid cytotoxic effects of the solvent.

Each plate was charged with a standard PPARalpha agonist, which waslikewise diluted in 11 different concentrations, in order to demonstratethe functioning of the assay in each individual plate. The assay platesare incubated in an incubator at 37° C. and 5% CO₂ for 24 h.

Day 3

The PPARalpha reporter cells treated with the test substances areremoved from the incubator, and the medium is aspirated off. The cellsare lyzed by pipetting 50 μl of Bright Glo reagent (from Promega) intoeach well of a 96 well microtiter plate. After incubation at roomtemperature in the dark for 10 minutes, the microtiter plates aremeasured in the luminometer (Trilux from Wallac). The measuring time foreach well of a microtiter plate is 1 sec.

Evaluation

The raw data from the luminometer are transferred into a Microsoft Excelfile. Dose-effect plots and EC50 values of PPAR agonists are calculatedusing the XL.Fit program as specified by the manufacturer (IDBS).

The PPARalpha EC50 values for the compounds of Examples 1 to 5 in thisassay are in the range from 1 μM to 5 μM. Compounds of the invention ofthe formula I activate the PPARalpha receptor.

Determination of EC50 values of PPAR agonists in the cellular PPARdeltaassay

Principle

The potency of substances which bind to human PPARdelta and activate itin an agonistic manner is analyzed using a stably transfected HEK cellline (HEK=human embryo kidney) which is referred to here as PPARdeltareporter cell line. In analogy to the assay described for PPARalpha, thePPARdelta reporter cell line also contains two genetic elements, aluciferase reporter element (pdeltaM-GAL4-Luc-Zeo) and a PPARdeltafusion protein (GR-GAL4-humanPPARdelta-LBD) which mediates expression ofthe luciferase reporter element depending on a PPARdelta ligand. Thestably and constitutively expressed fusion proteinGR-GAL4-humanPPARdelta-LBD binds in the cell nucleus of the PPARdeltareporter cell line via the GAL4 protein portion to the GAL4 DNA bindingmotifs 5′-upstream of the luciferase reporter element which is stablyintegrated in the genome of the cell line. There is only littleexpression of the luciferase reporter gene in the absence of a PPARdeltaligand if fatty acid-depleted fetal calf serum (cs-FCS) is used in theassay. PPARdelta ligands bind and activate the PPARdelta fusion proteinand thereby stimulate expression of the luciferase reporter gene. Theluciferase which is formed can be detected by means of chemiluminescencevia an appropriate substrate.

Construction of the PPARdelta Reporter Cell Line

The production of the stable PPARdelta reporter cell line is based on astable HEK-cell clone which was stably transfected with a luciferasereporter element. This step was already described above in the section“construction of the PPARalpha reporter cell line”. In a second step,the PPARdelta fusion protein (GR-GAL4-humanPPARdelta-LBD was stablyintroduced into this cell clone. For this purpose, the cDNA coding forthe N-terminal 76 amino acids of the glucocorticoid receptor (Accession# P04150) was linked to the cDNA section coding for amino acids 1-147 ofthe yeast transcription factor GAL4 (Accession # P04386). The cDNA ofthe ligand-binding domain of the human PPARdelta receptor (amino acidsS139-Y441; Accession # L07592) was cloned in at the 3′-end of thisGR-GAL4 construct. The fusion construct prepared in this way(GR-GAL4-humanPPARdelta-LBD) was recloned into the plasmid pcDNA3(Invitrogen) in order to enable constitutive expression by thecytomegalovirus promoter. This plasmid was linearized with a restrictionendonuclease and stably transfected into the previously described cellclone containing the luciferase reporter element. The resultingPPARdelta reporter cell line which contains a luciferase reporterelement and constitutively expresses the PPARdelta fusion protein(GR-GAL4-human PPARdelta-LBD) was isolated by selection with zeocin (0.5mg/ml) and G418 (0.5 mg/ml).

Assay Procedure and Evaluation

The activity of PPARdelta agonists is determined in a 3-day assay inexact analogy to the procedure already described for the PPARalphareporter cell line except that the PPARdelta reporter cell line and aspecific PPARdelta agonist was used as a standard to control testefficacy.

PPARdelta EC50 values in the range from 1 nM to >10 μM were measured forthe PPAR agonists of Examples 1 to 12 described in this application.Compounds of the invention of the formula I activate the PPARdeltareceptor.

Examples

The examples given in Table I serve to illustrate the invention, butwithout limiting it.

TABLE I

Example n R1 R2 R5 R6 R8 R9 R10 R11 1 0 — — H H —CF3 H H H 2 0 — — —CH3—CH3 CF3 H H H 3 0 — — H H —CF3 H —Cl H 4 0 — — —CH3 —CH3 —CF3 H —Cl H 51 H H H H —CF3 H —Cl H 6 0 — — H H —CF3 H H Cl 7 0 — — H H —CF3 —OCH3 HH 8 0 — — H H —Cl —CO—O—Ph H H 9 0 — — H H —Cl —CO—OH H H 10 0 — — H H—O—(CH2)2— H H 11 0 — — —(CH2)2—O—(CH2)2— —CF3 H H H 12 0 — — H H —CF3 HH —Ph—CF3 where R3, R4 and R7 = H.

The potency of some of the described examples are indicated in thefollowing table

PPARdelta PPARalpha Example EC50 (μM) EC50 (μM) 2 0.015 3.52 3 0.0031.11 5 0.035 1.64

Processes

The compounds of the general formula I according to the invention can beobtained as outlined to the reaction schemes below:

Process A

A compound of the general formula A-1 where R1, R2, R3, R4, R5, R6, R7,R8 and R9 are as defined is reacted with a sulfonylchloride of generalformula A-2 where R10 and R11 are as defined in the presence of a baseas triethylamine in a solvent as dichloromethane to give a compound ofthe general formula A-3. The compound of the general formula A-3 isreacted with hydroxylamine hydrochloride in the presence of a base astriethylamine in a solvent as tetrahydrofuran and methanol to obtain acompound of the general formula A-4. This reaction can be facilitated byheating the reaction mixture under microwave irradiation. This compoundof general formula A-4 is converted to the product of general formulaA-5 by reaction with phenylchloroformate in the presence of a base aspyridine or diisopropylethylamine followed by heating the reactionmixture with microwave irradiation to allow cyclization or alternativelyisolating the resulting intermediate and treating it with a base as1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent as acetonitrile.

Examples 1-2 were obtained according to process A.

Other compounds can be obtained accordingly or by known processes.

Process B:

A compound of the general formula B-1 where R1, R2, R3, R4, R5, R6, R7,R8 and R9 are as defined is reacted with a sulfonylchloride of generalformula B-2 where R10 and R11 are as defined in the presence of a baseas triethylamine in a solvent as dichloromethane to give a compound ofthe general formula A-3. The compound of the general formula A-3 isreacted with copper cyanide in a solvent as dimethylfomamide undermicrowave irradiation at a temperature e.g. 200° C. to give the cyanideof general formula B-4. The compound of the general formula B-4 isreacted with hydroxylamine hydrochloride in the presence of a base astriethylamine in a solvent as tetrahydrofuran and methanol to obtain acompound of the general formula B-5. This reaction can be facilitated byheating the reaction mixture under microwave irradiation. This compoundof general formula B-5 is converted to the product of general formulaB-6 by reaction with phenylchloroformate in the presence of a base aspyridine or diisopropylethylamine followed by heating the reactionmixture with microwave irradiation to allow cyclization or alternativelyisolating the resulting intermediate and treating it with a base as1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent as acetonitrile.

Examples 3-5 were obtained according to process B.

Other compounds can be obtained accordingly or by known processes.

Process C:

This process is used for synthesizing the building blocks A-1 and B-1,where R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined.

A boronic acid or a boronic ester of general formula C-1, where M1 andM2 can be independently hydrogen or alkyl (in the case of alkyl, M1 andM2 can form a ring system) and R8 and R9 are as defined is reacted withan arylbromide of general formula C-2, where R1, R2, R3, R4, R5, R6 andR7 are as defined and PG means a protecting group (as for example tert.Butyloxycarbonyl (BOC)), using a catalytic amount of a transition metalas for example palladium and a ligand as for example triphenylphosphinein the presence of a base as for example Na₂CO₃ in a solvent as forexample DMF/water, to obtain a compound of general formula C-3. Theprotecting group PG of compound of general formula C-3 is removed, incase of BOC for example by treatment with an acid as trifluoroaceticacid in a solvent as dichloromethane for example, to obtain the compoundof general formula A1=B1.

LIST OF ABBREVIATION

Ac acetyl AIBN 2,2′-Azobis(2-methylpropionitrile) Bn benzyl iBu isobutyltBu tert-Butyl BuLi n-butyllithium Bz benzoyl Cy cyclohexyl DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCI Direct chemical ionization (MS)DCM dichloromethane DMAP N,N-dimethylaminopyridine DMFN,N-dimethylformamide DMSO dimethylsulfoxide EE ethyl acetate eqequivalents ESI electrospray-Ionisation (MS) FG Leaving group Halhalogen HPLC High performance liquid chromatography LC-MS liquidchromatography coupled with mass-spectroscopy Me methyl MSmass-spectroscopy MsCl Methansulfonylchloride NBS N-Bromosuccinimide NMRNuclear magnetic resonance p para Pd/C palladium on carbon iPr isopropylnPr n-propyl Rf retention factor (TLC) tert Tertiary TBAF Tetrabutylammonium fluoride TFA Trifluoroacetic acid TLC Thin layer chromatography

Further compounds of the formula I can be prepared correspondingly or byknown processes.

The experimental procedures for preparing the examples mentioned aboveare described below:

Building block synthesis according to process C:

7-(4-Trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-isoquinolinetrifluoroacetate

4.63 g 4-(Trifluormethyl)phenylboronic acid was dissolved in 15 mlethanol and added to a mixture of 5.0 g1-(7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone in150 ml toluene and 54 ml of a 2 molar sodium carbonate solution. Thereaction mixture was degassed then 940 mgtetrakis(triphenylphosphine)palladium(0) was added and the mixtureheated under reflux for two hours. The cooled reaction mixture wasevaporated, the resulting residue was dissolved in 150 ml ethyl acetateand washed with 50 ml water and brine. The organic layer was dried overMgSO₄ and the solvent removed in vacuo. The resulting crude material waspurified by reversed phase HPLC to obtain 2.0 g7-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-isoquinoline as itstrifluoroacetate salt.

C16H14F3N.C2HF3O2 (391.3), MS(ESI+): 288.3 (M+H+).

The following examples were prepared according to process A:

Example 13-{4-[5-(4-Trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one

4-[5-(4-Trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile

1.25 g of commercially available 4-cyano-benzenesulfonyl chloride weredissolved in 35 ml dichloromethane. Then 760 mg5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole hydrochloride wereadded followed by 2.14 ml triethylamine. The mixture was stirred at roomtemperature for fifteen minutes. Then 100 ml of dichloromethane wereadded, the mixture washed with 40 ml water and brine and then dried overMgSO₄. The solvent was removed in vacuo. The resulting crude materialwas purified by reversed phase HPLC to obtain 517 mg of4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrileas amorphous lyophilisate. C22H15F3N2O2S (428.44), Rf(n-heptane:ethylacetate=1:1)=0.57.

N-Hydroxy-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzamidine

517 mg4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrilewere dissolved in a mixture of 10 ml tetrahydrofuran and 10 ml methanol.1.68 g hydroxylamine hydrochloride were added followed by the additionof 3.35 ml triethylamine. The reaction mixture was stirred at 65° C. foreight hours. The solvents were removed in vacuo and the resultingresidue poured into water and extracted five times with ethylacetate.The combined organic extracts were washed with brine, dried over MgSO₄and the solvent was evaporated in vacuo to obtain 550 mgN-hydroxy-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzamidineas an oil. C22H18F3N3O3S (461,47), MS (ESI): 462.2 (M+H⁺).

3-{4-[5-(4-Trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one

550 mgN-hydroxy-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzamidinewere dissolved in 10 ml dichloromethane. 0.17 ml pyridine and 0018 mlphenylchloroformate were added and the mixture stirred at roomtemperature for ten minutes. The mixture was diluted by the addition of20 ml acetonitrile and 0.89 ml 1,8-diazabicyclo[5.4.0]undec-7-ene wereadded. The mixture was stirred at room temperature for 15 minutes. Themixture was evaporated in vacuo and the resulting crude material waspurified by reversed phase HPLC to obtain 330 mg3-{4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-oneas an amorphous lyophilisate.

C23H16F3N3O4S (487.46), MS (ESI−): 486.2 (M−H⁺).

Example 23-{4-[3,3-Dimethyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-one

According to the method described for3-{4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-onein example 1,3-{4-[3,3-dimethyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-onewas obtained from commercially available 4-cyano-benzenesulfonylchloride and3,3-dimethyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole¹. ¹DE10335449, DE10335450, WO2005019169

C25H20F3N3O4S (515.51), MS (ESI−): 514.10 (M−H⁺).

The following examples were prepared according to process B:

Example 33-{2-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one

1-(4-Bromo-3-chloro-benzenesulfonyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-H-indole

1.79 g of commercially available 4-bromo-benzenesulfonyl chloride weredissolved in 35 ml dichloromethane. Then 1.85 g5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole hydrochloride wereadded followed by 2.14 ml triethylamine. The mixture was stirred at roomtemperature for fifteen minutes. Then 100 ml of dichloromethane wereadded, the mixture washed with 40 ml water and brine and then dried overMgSO₄. The solvent was removed in vacuo to obtain 2.48 g crude1-(4-bromo-3-chloro-benzenesulfonyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole.This material was used without further purification.

C21H14BrClF3NO2S (516.77), Rf(n-heptane:ethyl acetate=1:1)=0.61.

2-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile

2.48 g1-(4-bromo-3-chloro-benzenesulfonyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indolewere dissolved in 10 ml dimethylformamide. 2.15 g copper cyanide wereadded and the resulting mixture stirred under microwave irradiation at200° C. for thirty minutes. The mixture was diluted by addition of 100ml ethyl acetate and washed five times with portions of 50 ml saturatedammonium chloride solution. The organic layer was dried over MgSO₄ thenthe solvent was removed in vacuo to obtain 935 mg crude2-chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile.This material was used without further purification.

C22H14ClF3N2O2S (462.88).

3-{2-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one

According to the method described for3-{4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-onein example 1,3-{2-chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-onewas obtained from2-chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile.

C23H15ClF3N3O4S (521.91), MS (ESI−): 520.5 (M−H+).

Example 43-{2-Chloro-4-[3,3-dimethyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-one

According to the method described for3-{2-chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-onein example 3,3-{2-chloro-4-[3,3-dimethyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-onewas obtained from commercially available 4-bromo-benzenesulfonylchloride and3,3-dimethyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole². ²DE10335449, DE10335450, WO2005019169

C25H19ClF3N3O4S (549.96), MS (ESI+): 550.1 (M+H⁺).

Example 53-{2-Chloro-4-[7-(4-trifluoromethyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-one

According to the method described for3-{2-chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-onein example 3,3-{2-chloro-4-[7-(4-trifluoromethyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-onewas obtained from commercially available 4-bromo-benzenesulfonylchloride and7-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-isoquinolinetrifluoroacetate.

C24H17ClF3N3O4S (535.93), MS (ESI+): 536.1 (M+H⁺).

Example 63-{3-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one

According to the method described for3-{4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-onein Example 1,3-{3-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-onewas obtained from commercially available2-Chloro-4-cyano-benzenesulfonyl chloride and5-(4-Trifluoromethyl-phenyl)-2,3-dihydro-1H-indole.

C23H15ClF3N3O4S (521.04), MS (ESI−): 520.09 (M−H⁺).

Example 73-{4-[5-(2-Methoxy-4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one

According to the method described in process C and A,3-{4-[5-(2-Methoxy-4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-onewas obtained from commercially available2-Methoxy-4-trifluoromethyl-benzene-boronic acid,5-Bromo-2,3-dihydro-1H-indole and 4-Cyano-benzenesulfonyl chloride.

C24H18F3N3O5S (517.09), MS (ESI−): 516.00 (M−H+)

Example 85-Chloro-2-{1-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-2,3-dihydro-1H-indol-5-yl}-benzoicacid phenyl ester

According to the method described in process C and A,5-Chloro-2-{1-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-2,3-dihydro-1H-indol-5-yl}-benzoicacid phenyl ester was obtained from commercially available4-Chloro-2-(ethoxycarbonyl)benzene-boronic acid,5-Bromo-2,3-dihydro-1H-indole and 4-Cyano-benzenesulfonyl chloride.Under the conditions described for the synthesis of3-{4-[5-(4-Trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-onethe ethoxycarbonyl-group was converted to a phenoxycarbonyl-group.

C29H20ClN3O6S (573.08), MS (ESI−): 571.98 (M−H+)

Example 95-Chloro-2-{1-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-2,3-dihydro-1H-indol-5-yl}-benzoicacid

According to the method described in process C and A,5-Chloro-2-{1-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-2,3-dihydro-1H-indol-5-yl}-benzoicacid was obtained from commercially available4-Chloro-2-(ethoxycarbonyl)benzene-boronic acid,5-Bromo-2,3-dihydro-1H-indole and 4-Cyano-benzenesulfonyl chloride.Under the conditions described for the synthesis of7-(4-Trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-isoquinolinetrifluoroacetate the ethoxycarbonyl-group was converted to a carboxylacid-group.

C23H16ClN3O6S (497.04), MS (ESI−): 495.95 (M−H+)

Example 103-{4-[5-(2,3-Dihydro-benzofuran-5-yl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one

According to the method described in process C and A,3-{4-[5-(2,3-Dihydro-benzofuran-5-yl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-onewas obtained from commercially available2,3-Dihydro-benzofuran-5-boronic acid, 5-Bromo-2,3-dihydro-1H-indole and4-Cyano-benzenesulfonyl chloride.

C24H19N3O5S (461.10), MS (ESI−): 459.95 (M−H+)

Example 113-{4-[3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-oneStep 1:5-Bromo-3,3-(4-spiro-tetrahydropyran)-2-oxo-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester

To an ice-cold solution of 5-Bromo-2-oxo-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester (270 mg, 0.86 mmol) in dry DMF (7 mL) wascarefully added NaH (60%) (38 mg, 0.95 mmol). The mixture was stirredfor 30 min and then allowed to warm to room temperature.1-Iodo-2-(2-iodo-ethoxy)-ethane (395 mg, 1.2 mmol) was added andstirring was continued. After 4 h water (50 mL) was added and themixture was extracted with ethyl acetate. The organic phase was driedover MgSO₄ and the solvent was evaporated under reduced pressure. Theraw product was purified by silica gel chromatography to yield 207 mg ofa solid material.

Step 2: 5-Bromo-3,3-(4-spiro-tetrahydropyran)-1,3-dihydro-indol-2-one

A solution of5-Bromo-3,3-(4-spiro-tetrahydropyran)-2-oxo-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester (207 mg, 0.54 mmol) in CH₂Cl₂ (6.7 mL) andtrifluoroacetic acid (0.8 mL) was stirred at room temperature for 2 h.The solvents were evaporated under reduced pressure. The remaining oilwas used in the next step without further purification.

Step 3:3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one

A solution of5-Bromo-3,3-(4-Spiro-tetrahydropyran)-1,3-dihydro-indol-2-one (195 mg,0.69 mol), 4-Trifluoromethylphenyl-boronic acid (144 mg, 0.76 mmol),Cs2CO3 (675 mg, 2.07 mmol) and Tetrakis-triphenylphosphin-palladium(39.9 mg, 0.034 mmol) in DMF (10 mL) and water (3 mL) was heated to 90°C. for 6 h. The reaction mixture was allowed to cool to roomtemperature. Water (50 mL) was added and the mixture was extracted withethyl acetate (50 mL). The organic phase was dried over MgSO₄ and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to yield 285 mg solid material.

Step 4:3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole

To a solution of3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one(255 mg, 0.73 mmol) in dry THF (20 mL) was carefully added a 1 Msolution of LiAlH4 in THF (2.4 mL, 2.4 mmol). After 2 h at roomtemperature 100 μL of water, 100 μL of 15% NaOH solution and 100 μL ofwater were added successively. The mixture was stirred for 1 h, filteredand the solvent was evaporated under reduced pressure to yield 253 mg ofan oily material which was used without further purification in the nextstep.

Step 5:4-[3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile

To a solution of3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole(103 mg, 0.31 mmol) and triethylamine (149 μL, 0.93 mmol) in CH₂Cl₂ (5mL) was slowly added 4-Cyano-benzenesulfonyl chloride (62.3 mg, 0.31mmol). The mixture was stirred for 10 h at room temperature. Water (50mL) was added and the mixture was extracted three-times with ethylacetate (50 ml each). The organic phase was dried over MgSO₄ and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to yield 57 mg of solid material.

Step 6:4-[3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-N-hydroxy-benzamidine

To a solution of4-[3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrilein THF (9 mL) and methanol (9 mL) was added hydroxylamine hydrochloride(198.6 mg, 2.85 mmol) and triethylamine (400 μL, 2.85 mmol). The mixturewas heated to 90° C. for 2 h. The mixture was allowed to cool to roomtemperature, diluted with water (50 mL) and extracted three-times withethyl acetate (50 mL each). The organic phase was dried over MgSO₄ andthe solvent was evaporated under reduced pressure to yield 66 mg ofsolid material which was used directly in the next step.

Step 7:3-{4-[3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one

To an ice-cold solution of4-[3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-N-hydroxy-benzamidine(66 mg, 0.12 mmol) in CH₂Cl₂ (4 mL) and pyridine (12 μL, 015 mmol) wasslowly added a solution of phenylchloroformiate (19 μL, 0.15 mmol). Themixture was stirred for 15 min, the cooling bath was removed and thesolution was allowed to warm to room temperature. The mixture wasdiluted with CH3CN (4 mL) and DBU (93 μL, 0.62 mmol) was added. Themixture was stirred for 1 h. The solvents were evaporated under reducedpressure and the residue was purified by PR-chromatography to yield 10mg product.

C27H22F3N3O5S (557.12), MS (ESI−): 556.23 (M−H+)

Example 123-{4′-Trifluoromethyl-6-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-biphenyl-3-yl}-4H-[1,2,4]oxadiazol-5-one

3-{4′-Trifluoromethyl-6-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-biphenyl-3-yl}-4H-[1,2,4]oxadiazol-5-onewas synthesized from3-{3-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one(Example 6) by Suzuki-type reaction with 4-trifluoromethyl-phenylboronic acid under conditions described in Example 11.

C30H19F6N3O4S (631.10), MS (ESI−): 630.04 (M−H+)

1. A compound of formula I:

wherein n is 0 or 1 R1, R2, R3, and R4 are independently H, (C1-C8)alkyl, (C0-C4) alkylene-(C3-C7) cycloalkyl, or (C0-C4) alkylene-(C6-C10)aryl, wherein the alkyl and alkylene are independently unsubstituted or1- to 3-times substituted by F; R5 and R6 are independently H, (C1-C8)alkyl, (C0-C4) alkylene-(C3-C7) cycloalkyl, or (C0-C4) alkylene-(C6-C10)aryl, wherein the alkyl and alkylene are independently unsubstituted or1- to 3-times substituted by F, or R5 and R6 together with the carbonatom to which they are attached form a (C3-C7) cycloalkyl ring, whereinone carbon atom can be replaced by one heteroatom selected from O, S andN; R7 is H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-H, or (C3-C7) cycloalkyl, wherein the alkyl and alkylene areunsubstituted or 1- to 3-times substituted by F; R8 and R9 areindependently H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4)alkylene-H, (C3-C7) cycloalkyl, —CO—O—(C0-C4)-alkylene-H, CO—O-phenyl,or —C0-NR12R13, wherein the alkyl and alkylene are unsubstituted or 1-to 3-times substituted by F or NR12R13, and wherein the phenyl isunsubstituted or 1- to 3-times substituted by halogen, (C1-C4) alkyl,(C0-C4) alkylene-O—(C0-C4) alkylene-H, or NR12R13, or R8 and R9 togetherwith the carbon atoms to which they are bonded form a (C5-C7) cycloalkylring, wherein one carbon atom can be replaced by one heteroatom O, S, N;R10 and R11 are independently H, halogen, (C1-C8) alkyl, (C0-C4)alkylene-O—(C0-C4) alkylene-H, (C3-C7) cycloalkyl, or (C6-C10) aryl,wherein the cycloalkyl and aryl are unsubstituted or 1- to 2-timessubstituted by (C1-C4) alkyl, and wherein the alkyl and alkylene areunsubstituted or 1- to 3-times substituted by F; and R12 and R13 areindependently H, (C1-C6) alkyl; or a stereoisomer or tautomer thereof,or a physiologically acceptable salt thereof.
 2. The compound accordingto claim 1, wherein R9 is at position 2; or a stereoisomer or tautomerthereof, or a physiologically acceptable salt thereof.
 3. The compoundaccording to claim 1, wherein R11 is at position 3′; or a stereoisomeror tautomer thereof, or a physiologically acceptable salt thereof. 4.The compound according to claim 1, wherein R11 is at position 3′; andR10 is H; or a stereoisomer or tautomer thereof, or a physiologicallyacceptable salt thereof.
 5. The compound according to claim 1, wherein nis 0 or 1; R1, R2, R3 and R4 are H; R5 and R6 are independently H or(C1-C6) alkyl, or R5 and R6 together with the carbon atom to which theyare attached form a (C5-C6) cycloalkyl ring wherein one carbon atom canbe replaced by one heteroatom selected from O and N; R7 is H; R8 is CF₃,or Cl, R9 is at position 2, and R9 is H, F, O—(C1-C4) alkyl, COOH,CO—O-phenyl, O—(C1-C4) alkyl-NR12R13, CO—O—(C1-C4) alkyl-NR12R13, orCO—NH—(C1-C4) alkyl-NR12R13, or R8 and R9 together with the carbon atomsto which they are attached form a (C5-C6) cycloalkyl ring, wherein onecarbon atom is replaced by one heteroatom O; R10 is H, Cl, F, or CH₃;R11 is H, Cl, or phenyl-CF₃; and R12 and R13 are (C1-C4) alkyl; or astereoisomer or tautomer thereof, or a physiologically acceptable saltthereof.
 6. The compound according to claim 1, wherein n is 0 or 1; R1,R2, R3 and R4 are H; R5 and R6 are independently H or (C1-C6) alkyl; R7is H; R8 is CF₃; R9 is H; R10 is Cl; and R11 is H; or a stereoisomer ortautomer thereof, or a physiologically acceptable salt thereof.
 7. Thecompound according to claim 1, wherein n is 0 or 1; R1, R2, R3 and R4are H; R5 and R6 are independently H or CH₃; R7 is H; R8 is CF₃; R9 isH; R10 is Cl; and R11 is H; or a stereoisomer or tautomer thereof, or aphysiologically acceptable salt thereof.
 8. The compound according toclaim 1, wherein n is 0; or a stereoisomer or tautomer thereof, or aphysiologically acceptable salt thereof.
 9. The compound according toclaim 1, which is3-{4-[5-(4-Trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one;3-{4-[3,3-Dimethyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-one;3-{2-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one;3-{2-Chloro-4-[3,3-dimethyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-one;3-{3-Chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one;3-{4-[5-(2-Methoxy-4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one;5-Chloro-2-{1-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-2,3-dihydro-1H-indol-5-yl}-benzoicacid phenyl ester;5-Chloro-2-{1-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-2,3-dihydro-1H-indol-5-yl}-benzoicacid;3-{4-[5-(2,3-Dihydro-benzofuran-5-yl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one;3-{4-[3,3-(4-Spiro-tetrahydropyran)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-phenyl}-4H-[1,2,4]oxadiazol-5-one;or3-{4′-Trifluoromethyl-6-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-biphenyl-3-yl}-4H-[1,2,4]oxadiazol-5-one;or a stereoisomer or tautomer thereof, or a physiologically acceptablesalt thereof.
 10. A pharmaceutical composition comprising the compoundaccording to claim 1, or a stereoisomer or tautomer thereof, or aphysiologically acceptable salt thereof, in combination with apharmaceutically acceptable carrier or excipient.
 11. The pharmaceuticalcomposition according to claim 10, further comprising an additionalactive substance, wherein the additional active substance has afavorable effect on metabolic disturbance or a disorder frequentlyassociated therewith.
 12. The pharmaceutical composition according toclaim 10, further comprising an antidiabetics.
 13. The pharmaceuticalcomposition according to claim 10, further comprising a lipid modulator.14. A pharmaceutical composition comprising the compound according toclaim 2, or a stereoisomer or tautomer thereof, or a physiologicallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable carrier or excipient.
 15. A pharmaceutical compositioncomprising the compound according to claim 3, or a stereoisomer ortautomer thereof, or a physiologically acceptable salt thereof, incombination with a pharmaceutically acceptable carrier or excipient. 16.A pharmaceutical composition comprising the compound according to claim4, or a stereoisomer or tautomer thereof, or a physiologicallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable carrier or excipient.
 17. A pharmaceutical compositioncomprising the compound according to claim 5, or a stereoisomer ortautomer thereof, or a physiologically acceptable salt thereof, incombination with a pharmaceutically acceptable carrier or excipient. 18.A pharmaceutical composition comprising the compound according to claim6, or a stereoisomer or tautomer thereof, or a physiologicallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable carrier or excipient.
 19. A pharmaceutical compositioncomprising the compound according to claim 7, or a stereoisomer ortautomer thereof, or a physiologically acceptable salt thereof, incombination with a pharmaceutically acceptable carrier or excipient. 20.A pharmaceutical composition comprising the compound according to claim8, or a stereoisomer or tautomer thereof, or a physiologicallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable carrier or excipient.
 21. A method for treating a disorder offatty acid metabolism, glucose utilization disorder, a disorder in whichinsulin resistance is involved, diabetes mellitus or a squelaeassociated therewith, dyslipidemia or a squeal associated therewith, acondition which is associated with metabolic syndrome, or demyelinatingor another neurodegenerative disorder of central or peripheral nervoussystem, in a patient in need thereof, comprising administering to thepatient a pharmaceutically effective amount of the compound according toclaim 1, or a stereoisomer or tautomer thereof, or a physiologicallyacceptable salt thereof.
 22. A process for preparing a pharmaceuticalcomposition comprising the compound according to claim 1, or astereoisomer or tautomer thereof, or a physiologically acceptable saltthereof, in combination with a pharmaceutically acceptable carrier orexcipient, which comprises mixing the compound according to claim 1, orthe stereoisomer or tautomer thereof, or the physiologically acceptablesalt thereof, with the pharmaceutically acceptable carrier or excipientand bringing this mixture into a form suitable for administration.
 23. Acompound, which is3-{2-Chloro-4-[7-(4-trifluoromethyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-one;or a stereoisomer or tautomer thereof, or a physiologically acceptablesalt thereof.
 24. A pharmaceutical composition comprising3-{2-Chloro-4-[7-(4-trifluoromethyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-sulfonyl]-phenyl}-2H-[1,2,4]oxadiazol-5-one;or a stereoisomer or tautomer thereof, or a physiologically acceptablesalt thereof, in combination with a pharmaceutically acceptable carrieror excipient.